Fast Track Drug Development
Programs — Designation, Development, and Application Review
The Food and Drug Administration Modernization Act of 1997 (FDAMA) includes Section 112,
“Expediting study and approval of fast track drugs.”
"This section mandates the Agency to facilitate the development and expedite review of drugs and biologics intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. Fast track adds to existing programs, such as accelerated approval, the possibility of a “rolling submission” for a marketing application. An important feature of fast track is that it emphasizes the critical nature of close early communication between the FDA and sponsor to improve the efficiency of product development."
Linking Viruses & Cancer
Viruses and cancer are linked, but why?
Some say immune response to infection is the mechanism that turns infectious organisms into cancer
by Marie Rosenthal, Editor in Chief
February 2004, Infectious Disease News
NEW YORK – More than a dozen viruses have been linked with various cancers, although no one is entirely sure why this phenomenon occurs.
It is probably related to the immune responses to infection. Perhaps, immune modulators change the host gene in some people, which increases their risk for cancer development. In other words, “… the stuff that goes on in the environment of the infected cell – what we call the milieu – that deals not only with the release of immune modulators that causes the tissue to get red and swollen and hot – but causes some dysfunction,” explained James J. Goedert, MD, chief of the viral epidemiology branch, and senior investigator at the National Cancer Institute (NCI).
In some cases, he added, superinfection may release reactive oxygen species that damage DNA and alter the host gene expression.
Finding a link between infection and cancer has been difficult because finding a virus in a cancer does not prove causation, according to the American Society of Clinical Oncology (ASCO), which sponsored a seminar on the topic here. To make the relationship even harder to prove, not every infected individual will develop cancer, and uninfected people can develop the same cancer.
However, there are clear links between viruses and cancers, said Goedert. Overlapping epidemiology between viruses and cancers can be a clue to this link. Incidence of certain cancers is highest where specific infectious diseases are endemic. However, there is no way to know which person with a specific infection will develop cancer, said Goedert.
One way to understand the link better is to look at infections that are positively linked to cancers and try to determine why, he said.
HBV, HCV and liver cancer
Hepatocellular carcinoma accounts for more than 90% of primary liver cancers and is one of the most common malignancies in the world, accounting for about 500,000 cancers a year, according to Andrew X. Zhu, MD, PhD, assistant physician at Massachusetts General Hospital in Boston.
“This is a disease for which we have multiple treatment options, yet the prognosis remains dismal,” he said.
Although the incidence has been higher in developing countries than developed ones, this trend is changing, and hepatocellular carcinoma incidence and mortality in the United States has increased twofold between 1975 and 1998. “Although this increase is affecting all ethnic and most age groups, white men between 45 and 54 years of age have the fastest increase,” Zhu explained.
This increase, in part, is due to hepatitis B and C. There are 300 million people worldwide with chronic hepatitis B virus (HBV) infection, with 1.25 million chronically infected people in the United States. There are about 100 million people worldwide with hepatitis C (HCV), and 4 million people chronically infected with HCV in the United States.
“We do know from the epidemiological studies that there is a strong association between HBV–HCV infection and hepatocellular carcinoma development. We can develop different sophisticated testing to look for the HBV and HCV molecules in hepatocellular carcinoma. They are definitely present,” said Zhu.
The mechanism that turns HBV or HCV into hepatocellular cancer is a complicated interaction between specific viral gene products and the host immune system, as well as the underlying genomic stability. There is speculation that screening for the viruses may be beneficial in endemic areas to prevent cancer. This approach, however, has not been validated in a randomized control study.
Prevention appears to be a rational approach for these diseases because there are well-defined risk factors, Zhu said. In addition, there is an effective vaccine against HBV. However, the search for an HCV vaccine has been elusive.
“This virus is fairly smart. We have the different genotypes and quasi-species, so the virus has sophisticated ways of evading the immune system. Even if you develop one vaccine, probably it won’t be as effective as you think,” Goedert explained. “You may have to design a specific vaccine depending on the genotype in the particularly endemic area.”
Understanding the biology of how the cancer develops in the cells, and developing better prevention and treatment programs “will continue to represent very key strategies to prevent hepatocellular cancer,” said Zhu.
HPV and multiple cancers
Human papillomavirus (HPV) is the most common sexually transmitted disease in the United States, said Maura L. Gillison, MD, PhD, assistant professor of oncology at Johns Hopkins School of Medicine in Baltimore.
“There are more than 600,000 cases of cancer worldwide that can be attributed to HPV infection,” Gillison said. Most of the cancers are cervical, vulvar cancer, penile and a.n.a.l squamous cell carcinomas, but over the last three years there’s been “quite an explosion of data” to implicate HPV in head and neck cancers, she added.
Although cervical cancer incidence in the United States has declined because of effective screening, a.n.a.l and tonsillar cancer incidence has increased. “Cervical cancer is unique among the cancers that are associated with HPV in that HPV infection is necessary, although not sufficient for the development of cervical cancer. In all other cancers where there is an established association, it will likely be a subset of cancers at that anatomic site that are etiologically related to HPV,” she said.
The 130 types of HPV fall into cutaneous and mucosal types; the mucosal or genital HPVs are further divided into those that are strongly associated with cancer. The highest risk types are HPV16, 18, 31 and 33.
In cervical cancer, the cancer-causing types of HPV encode two oncoproteins, E6 and E7. HPV-E6 binds to another cellular protein that targets p53 for degradation. p53 is the tumor-suppressor gene that is most common in human malignancies. HPV-16 E7 binds to hypophosphorylated retinoblastoma protein and targets that protein for degradation. This releases transcription factors that are important in the progression of the cell cycle from G1 to S, explained Gillison.
“That means infection of a cell by a high-risk HPV type is functionally analogous to mutating two tumor suppressor genes that are important in the development of human malignancies,” she said. This causes a “loss of cell control, of DNA damage repair, progression through the cell cycle, genomic integrity, cellular differentiation and cell death. All of those contribute to how HPV causes cancers to progress,” she said.
A recent study in Cancer by Taiwanese researchers found that the presence of HPV-31 was an independent predictor of increased survival in patients with cervical cancer. As a result of their data, HPV genotyping of cervical carcinomas may have profound implications for future management of cervical cancer patients, they concluded.
Sexual behavior, including oral sex for head and neck cancers, is the single greatest risk factor for HPV exposure. “And if it wasn’t the person’s behavior, it’s the behavior of the sexual partner,” she said.
Immune state, genetic makeup and the type of HPV are important factors that determine whether infection will clear or become cancer. Smoking and long-term use of oral contraceptives may increase the likelihood that HPV infection will persist.
Most head and neck cancers that arise in the nonsmoker and nondrinker are associated with HPV. HPV-DNA is found in 20% of all head and neck cancers, and up to 70% of tonsillar cancers are HPV-associated. “We know that there is virtually an epidemic of tonsillar cancer in the United States that’s unexplained, and I think we’ve now explained it,” Gillison said.
There is work being done on HPV vaccines, however, they do not seem to be effective against all types of HPV, and will probably be type specific.
H. pylori and gastric cancers
Helicobacter pylori infection tends to be acquired in childhood and is lifelong unless antibiotic therapy eradicates the organism, said Charles S. Rabkin, MD, MSC, senior investigator, viral epidemiology at NCI.
It is almost universally present in the developing world where infection rates exceed 85% in most adults. In contrast, the risk of infection in the West is lower, so that infection rates of 10% to 20% are now being seen in adults.
No one completely understands how the infection is acquired, but there does appear to be person-to-person transmission, and the infection can cluster among family members.
H. pylori has developed good techniques for surviving in the acidic environment of the stomach, which kills most other organisms. These techniques, including the secretion of urease and lipopolysaccharide (LPS), help induce the diseases that are associated with helicobacter.
As it colonizes the mucosal layer, LPS and peptides secreted by H. pylori pass through the epithelial layer under the stomach lining. This attracts neutrophils and monocytes that release a number of factors, such as tumor necrosis factor, oxygen-free radicals, prostaglandins and interleukin-1 beta, damaging the gastric lining.
“So this is an indirect effect. It’s not direct contact with H. pylori, but rather it’s an effect of the secreted mediators that cause the gastric inflammation – the first step in the process of disease caused by helicobacter,” Rabkin said.
It’s a universal phenomenon that people with helicobacter infection develop gastritis, yet most are asymptomatic. Ulcer disease occurs in around one in 10 people who have H. pylori infection, and gastric lymphoma and gastric carcinoma happen in just 1% to 2% of people who are infected over many decades.
Although overall gastric cancer has been decreasing, adenocarcinoma of the esophagus is increasing. “The noncardia cancers are showing the declines, and that makes up the bulk of gastric cancer. This is what drives the rate of gastric cancer overall,” he said. “But very worryingly, the cardia cancers both in men and women and in whites and in blacks have been on the increase,” Rabkin said.
HTLV-1 and lymphoma
There are about 15 million to 20 million cases of human T-cell leukemia virus (HTLV-1) worldwide, said Francine M. Foss, MD, director of lymphoma and experimental therapeutics at Tufts-New England Medical Center. This was the first human retrovirus identified, and was isolated in 1980 from a patient with T-cell lymphoma. In 1982, researchers provided evidence that HTLV-1 could lead to the development of adult T-cell leukemia-lymphoma.
“In endemic areas, many people carry this virus, and it seems to be clustered in families and in women, suggesting that the transmission occurs more frequently from men to women and from women to children than it does from women to men,” Foss said.
An HTLV-1 carrier has a lifetime risk of developing acute leukemia of about 1% to 4%, so while the incidence of this virus is high in a population, the percentage that will get cancer is relatively low.
HTLV-1 is an RNA virus. Reverse transcriptase copies the genetic information into DNA once the virus has entered the host cell. This DNA copy (a provirus) is inserted into the chromosomal DNA of the host cell, where it becomes a part of the cell’s genetic makeup, Foss explained.
When this virus is in the cells and replicating, “there is an increased propensity for secondary genetic events and eventually you would select out a clone of cells that’s capable of independent or autonomous growth. It is thought that this may be how patients develop leukemia,” Foss said.
Insertion of the HTLV–1 provirus into the host-cell genome may disrupt normal cellular genes, which could contribute to cancerous changes in the cell. But this would not be sufficient to transform infected cells into cancer cells. The development of cancer in an infected cell requires changes in expression or damage to multiple other host cell genes, according to ASCO. However, the specific mechanisms by which HTLV-1 infected cells become cancerous are still being researched, according to Foss.
HHV8, AIDS and KS
Even though Kaposi’s sarcoma (KS) had been associated with HIV infection, there were numerous clues that there was a second virus involved, said NCI’s Goedert, and eventually human herpes virus 8 (HHV8) was found to cause KS.
Classic KS occurs in older men of southern European and Middle Eastern origin. Endemic KS occurs in Africa. Children as well as adults can be affected. Iatrogenic KS occurs in organ transplants. Transplant recipients are 150 to 200 times more likely to develop KS than immunocompetent patients. AIDS-related KS is the most common form of this disease today.
Because KS is more common among the immunocompromised, researchers think that the immune system prevents progression to KS in normal people. About 5% of the people in the United States appear to be infected with HHV-8, yet the incidence of KS is estimated to be around 1.5 per million. Among elderly people in the Mediterranean who have HHV-8, but not HIV, classical KS develops in about one in 10,000 people annually. In parts of Africa, where 50% of the population has HHV-8 and 10% or more are coinfected with HIV, KS is the most common form of cancer.
“So the risk of getting the disease if you have AIDS and you have the virus in the blood, it’s extraordinarily high,” he said.
Before highly active antiretroviral therapy (HAART), about 35% of men with HHV-8 and HIV developed KS within 10 years. After HAART, there was “an abrupt reduction in KS risk among people with AIDS. It’s truly stunning and truly profound in terms of the impact that HAART has had,” Goedert said.
Researchers continue to look at possible links between infections and cancers. “I think it’s almost certain there will be some additional infections, particularly viruses, found that cause cancer in humans,” explained Goedert.
If links can be found with clear mechanisms of action, researchers may be able to find cures for cancers by preventing or treating the infection.
For more information:
Johnson BE, Goedert JJ, Zhu AX, et al. The virus-Cancer Link: Examining the Role of Viruses in the Development of Cancer. American Society of Clinical Oncology. Special Media Event: Meet the Experts. Dec. 10, 2003. New York City.
Autoimmune Diseases Share
08 September 2004
Researchers have found that antibodies from patients with rheumatoid arthritis are able to induce cytokine production through the insulin-like growth factor-1 receptor (IGF-1R) pathway in a fashion identical to that previously shown for antibodies from patients with Grave’s disease.
Investigators from the University of California, Los Angeles (USA), reported in the September 1, 2004, issue of the Journal of Immunology that antibodies from individuals with active rheumatoid arthritis (RA-IgG) stimulate their synovial fibroblasts to express the CD4-specific T lymphocyte chemoattractant, IL-16, and RANTES, a C-C chemokine. This induction, which is identical to that previously reported for patients with Grave’s disease, is mediated through the insulin-like growth factor-1 receptor (IGF-1R) pathway. Antibodies from individuals without known autoimmune disease fail to elicit this chemoattractant production.
If these findings can be extended to other autoimmune disorders such as multiple sclerosis and lupus, it may be possible to develop a common therapeutic strategy for these conditions.
Senior author Dr. Terry J. Smith, a professor in the division of molecular medicine at UCLA said, “It is possible that these findings will allow us for the first time to interrupt the disease process before any lasting damage occurs.”
***Re ADVR and AVR118: If anyone
missed the presentation by our CEO and President, Dr. Elma Hawkins, at The
Wall Street Analyst Forum Conference on September 13, it will be available
for 30 days thereafter.
Dr. Hawkins discussed the progress the company is making with its flagship product, AVR118, to biotech and pharmaceutical analysts.
You can hear it at the following web address:
lovingitall0's: "Fast Track" Status
Seems Feasible For ADVR's IND Application !!!
According to the below excerpt taken from the FDA link you provided, it would be permissible for ADVR to request a Fast Track Designation for AVR118 at the time of it's IND submission , contrary to past statements made on this forum that it could not !!!
If fast track status is accepted by the FDA , wouldn't that be a huge lift for our pps !!! I believe Elma IS heading in the direction of Fast Track for AVR118 !!!
Only a few more months and we will find out !!!
FAST TRACK was one of Elma's focused "characteristics criteria" in choosing an indication for an IND :
- Address an important medical need
- Prior experiences in the indication
- Sufficient patient population
- Small sample size
- Clinical trials of short duration
- Clear, objective, validated endpoints
- *** ELIGIBLE FOR SPECIAL REGULATORY CONSIDERATIONS ***
- Ideally minimal competition
from which cometh the crucial , planned , methodical, strategic and focused decision announced in ADVR's last PR:
"From the successful Pre-IND Meeting with FDA , Advanced Viral Research Corp. believes it is well positioned to submit an IND application for the INJECTABLE USE OF AVR118 IN PATIENTS WITH CANCER by the end of 2004 or beginning of 2005."
From your link :
"PROCESS FOR DESIGNATING A DRUG FOR THE FAST TRACK DRUG DEVELOPMENT PROGRAM
The general procedures applicable to the submission and review of fast track designation requests are described below.
Timing of Submission
A sponsor may submit a request for fast track designation at the time of original submission of its IND, or at any time thereafter prior to receiving marketing approval of its BLA or NDA. Note that the IND and potential fast track designation may be discussed prior to an IND submission in a pre-IND meeting, but a decision on designation would await submission of the IND. Although benefits associated with fast track designation may occur throughout the drug development process, from the early IND submission to evaluation of a marketing application, as a practical matter, requests should ordinarily occur no later than the sponsor's pre-BLA/NDA meeting with the Agency, as many of the benefits of fast track designation will no longer be applicable after that time. "
ITS ALL COMMING TOGETHER QUITE METHODICALLY THANKS TO DR. ELMA S. HAWKINS!!!
(Voluntary Disclosure: Position- Long; ST Rating- Strong Buy; LT Rating- Strong Buy)
"it would be permissible for ADVR
to request a Fast Track Designation for AVR118 at the time of it's IND
I would only hope ADVR, if indeed it does request Fast Track status from the FDA, WHEN the IND "application" is submitted, would NOT be foolish enough to declare such -- until AFTER the application is approved! I would hate for shareholders to get their hopes up and then after the customary WAIT of 30 days, find out the FDA says....NO!
Just my thoughts on the matter.
Well, I'll be darned,
FastTrackStatus is back, under a new and improved and non-censored moniker.
He is asking for Gator, Allen and our very own Blueeyes. Did someone mention
Bill Gates????... Golly gee, it's been a while now (since this guy's
appearance here......re: the China-Patent HIV approval) but does anyone
remember who was "proclaimed" to be Gates' broker???....LOL. Whoa
boy......the pump....she's a coming!!!....I feel it in me bones!!
"do you see anything on the horizon
for ADVR besides my BILL GATES delusions?"
Please, if I may respond for Julie:
Re: ADVR...I see many things on the horizon. Not so soon and not so fast but in the future if you can last.
BTW: as for RMSG, I can only say that up .24 in one day! It should only happen to us!
I haven't had the time to research the others yet.
But, hey....Goooooood luck!
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This profile is not without bias,
and is a paid release.
I still believe we're headed up.
Lookin 4 the INDA ;)
Blocking Nuclear Factor-Kappa B
Turns Inflammation Into Cancer Killer
NEW YORK (Reuters Health) Sept 24 - Blocking nuclear factor kappa-B (NF-KB) turns inflammation-induced tumor growth into inflammation-induced tumor shrinkage by allowing TNF-related apoptosis ligand (TRAIL) free rein to destroy abnormal cells, a new study in mice shows.
NF-KB, which operates within cancer cells, responds to inflammatory stimuli by releasing tumor growth signals, a process mediated by tumor necrosis factor-alpha (TNF-alpha). While in vitro studies had suggested TNF-alpha prevented tumor growth, Dr. Michael Karin of the University of California at San Diego told Reuters Health, this study shows that in vivo, it actually acts more like a tumor growth factor.
In the current study, reported in the September issue of Cancer Cell, Dr. Karin and his colleagues used mice given breast or colon cancer cells, some of which had been treated with an NF-KB inhibitor. Regardless of whether or not NF-KB was blocked, the cells grew and spread to the lung.
Then the animals were given lipopolysaccharide to induce an inflammatory response. Among animals with active NF-KB, inflammation boosted TNF-alpha production and eventually increased tumor growth. But blocking either TNF-alpha or NF-KB in the presence of inflammation allowed TRAIL to kill tumor cells, so tumors in these mice actually shrank.
Past research on TRAIL shows that it promotes apoptosis, but does not strongly induce inflammation, Dr. Karin and his team note in the September issue of Cancer Cell.
In a press release, first author Dr. Jun-Li Luo points out that inflammation induces the production of NF-KB, TNF-alpha and TRAIL. But under normal circumstances the tumor-growth-stimulating effects of the first two molecules outweigh TRAIL's tumor-fighting powers.
The findings suggest TRAIL-promoting drugs such as interferon could be particularly effective in fighting cancer when added to NF-LB-blockers, Dr. Karin said. "I think TRAIL has a great potential, but it may not work all that well by itself," he noted. The key, he added, is not to see new cancer drugs like these as monotherapies--a view that the current US drug approval system encourages--but in combination.
Drugs that inhibit the enzyme I-kappa-B kinase beta, which is required to activate NF-KB, are currently in preclinical development, Dr. Karin said.
Cancer Cell 2004;6:297-305.
Does AVR118 inhibit I-kappa-B
I sure hope so. This is interesting
UCSD Researchers Discover New Role
For Immune-Response Enzyme
Aug. 23, 2001
When viruses or bacteria assault the body, the immune system marshals its army of attack cells to ward off invaders. But sometimes, that arsenal of immune cells mistakenly ravages the body’s own tissues, leading to a variety of autoimmune diseases such as rheumatoid arthritis, SLE (lupus) and multiple sclerosis.
Now, a team of scientists led by Michael Karin, Ph.D., UCSD professor of pharmacology and member of the UCSD Cancer Center, have discovered a new immunological pathway that opens a new avenue of research, with the potential for preventing autoimmune diseases and some lymphomas, without compromising the body’s immune defenses.
Published in the August 24, 2001 issue of the journal Science, researchers from UCSD, Germany and Pennsylvania describe a previously unknown role for an enzyme call I-kappa-B kinase alpha (IKKa). Scientists have known that IKKa’s cousin – an enzyme called IKK beta (IKKb) – is capable of acting without IKKa in initiating a molecular chain of events triggering the body’s immune response. It was thought that IKKa’s only role was in an unrelated function, the formation of the skin’s outer layer.
With studies in test tubes and mice, researchers have now learned that IKKa also plays a role in the immune system, but acts independently of IKKb by taking a separate molecular pathway. IKKa is essential for development of B cells, one of the infection-fighting white cells that produce antibodies to invading pathogens, and for the formation of certain lymphoid organs and immune response genes.
Importantly, the scientists found that blocking the action of IKKa did not stop the IKKb-dependent immune response. It’s this difference that offers a new research approach for autoimmune diseases. With additional work, researchers may find agents that can block only IKKa and over-expressed immune reactions that attack the body’s own tissues, while protecting the immune system response with IKKb.
Karin noted that “if you can make specific inhibitors of IKKa that do not inhibit IKKb, we should be able to treat certain autoimmune disease without bringing on complete immunodeficiency. Right now, the treatment for autoimmune diseases is use of toxic drugs that knock out both B and T cells, necessary elements of the immune response.”
Karin adds that the chemical chain of events initiated by IKKa is a molecular pathway also known to play a role in B cell lymphomas. By finding an inhibitor of IKKa, the scientists see potential for new treatments for this form of lymphoid cancer, as well as autoimmunity.
The new work in the Karin lab is a continuation of several years’ investigation into the role of IKK, a multi-component protein complex identified in 1996 by the Karin team. Through that landmark work, and work done elsewhere, it was shown that IKK is responsible for controlling the body’s inflammatory response, the first line of defense from microbial infections. In 1999, the Karin group found that IKK’s beta subunit, IKKb, is essential for activation of the entire IKK complex by responding to chemical signal that trigger inflammation.
In response to infection and inflammation, IKKb attacks and degrades a molecule that holds captive an important family of proteins called NF-kB. Once freed, NF-kB generates the body’s immune response. Although IKKa does not participate in this molecular chain of events, the research team discovered that IKKa controls the processing of one of the NF-kB proteins called NF-kB2, which is essential for development of B cells. In addition, they found that IKKa helps in the formation of germinal centers, areas within the lymph nodes where B cells rapidly divide and produce highly specific antibodies.
While both the beta and alpha subunits of IKK play a role in the immune response, the Karin team notes that the absence of IKKa can be compensated by IKKb in most cell types leading to normal NF-kB activation and defense against invading pathogens.
Authors of the Science paper in addition to Karin were first author Uwe Senftlebon, M.D., UCSD Department of Pharmacology and Clinic for Anesthesiology, University of Ulm, Germany; Yixue Cao, Ph.D., Florian R. Greten, M.D., Giuseppina Bonizzi, Ph.D., Yi Chen, Ph.D., and Yinling Hu, Ph.D., UCSD Department of Pharmacology; Gutlan Xiao, Ph.D., Abraham Fong, B.Sc., and Shao-Cong Sun, Ph.D, Pennsylvania State University College of Medicine; and Gertraud Krahn, M.D., Ph.D., UCSD Department of Pharmacology and University of Ulm, Germany Department of Dermatology.
The research was supported by postdoctoral fellowships from the Deutsche Forschungsgemeinschaft, the California Breast Cancer Research Project, Human Frontier Science Program, the Arthritis Foundation, and grants from the National Institutes of Health and the California Cancer Research Program.
Anyone know how ejacki is doing? He
was taking AVR118.
Doctor Works to Fight 'Plague of
the Century' in China
Houston Chronicle (09.26.04) - September 28, 2004
In a visit last week to Houston, AIDS drug cocktail innovator Dr. David Ho said that countries like China that face a growing AIDS epidemic should circulate disease information and focus on changing behavior while the world searches for an AIDS vaccine. Asked if a vaccine would be required for eradicating HIV worldwide, Ho singled out Senegal and Thailand as examples where, in the short term, "good old-fashioned public health measures can slow down an epidemic."
Countries at risk "have a window of opportunity to make a difference, but it is closing," said Ho. "It's unacceptable that half of the Chinese population has never heard of AIDS," he said.
A public service announcement featuring National Basketball Association superstar Yao Ming and HIV-positive veteran player Magic Johnson will be presented in China when NBA games are played there in October, Ho said. "They are shaking hands and eating together," Ho said of the PSA. "In the commercial Yao shows Magic how to use chopsticks. It should help break down some of the stigma around the disease. The overall message is very simple - go out and learn more about HIV and AIDS, and how to protect yourself."
Asked how much he blames drug companies for not making AIDS drugs available cheaply worldwide, Ho said, "Pharmaceutical companies got into HIV treatment without hesitation and made huge contributions.... There is a moral obligation to get these drugs to the developing world, but to do that you almost have to give them away at cost.... These companies have taken a lot of bad public relations.... I see many disincentives for pharmaceutical companies to stay in this arena, and that concerns me."
In response to treatment-related complacency seen among some gay men, Ho said that prevention messages must be continually renewed. "These drugs are not perfect. There are side effects and other costs. There is an accumulation of consequences. All of this comes at a high cost, and people need to understand that."
i support only ADVR and those who
support it, i do not support the clown and others who post filth even it
they support it, and i am not wild about harry
After 20 years, AIDS vaccine still
seems a distant dream
USA Today, Sept. 28, 2004
When AIDS was young, researchers pinned their hopes of ending the epidemic on the speedy discovery of a vaccine. Twenty years later, they realize their work is still just beginning.
This recognition comes from a steady drumbeat of discouraging results, most recently this month at the 2004 AIDS Vaccine Conference in Switzerland, and in July at the 15th International AIDS Conference in Bangkok.
"We're dealing with a very formidable scientific challenge," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. "This is probably going to turn out to be the most difficult vaccine to develop in the history of vaccine research."
Unlike other viruses, AIDS doesn't produce immunity in people who are exposed to it because it attacks the immune system itself. People who are already infected with one strain of HIV are still vulnerable to infection with others, a catastrophe known as "super infection." As a result, most of the vaccines tried so far have failed to live up to expectations, researchers say.
The most widely publicized flop was VaxGen's prototype AIDSVAX, which failed last year in large-scale human trials of 8,000 people in North America and Thailand after years of costly research.
Almost two-dozen prototype vaccines are being tested in humans, compared with seven just two years ago. Eleven of them are in the U.S. government-sponsored HIV Vaccine Trials Network. Many of them use kaleidoscopic combinations of HIV genes or proteins - diced up so they can't reproduce and give people AIDS - packaged in a wide array of weakened viruses. So far, researchers say they haven't found any combo that reliably generates potent enough immune responses.
As a result, they say, AIDS vaccine research is at a crossroads, with once-promising approaches falling by the wayside and little certainty about where to go next.
"Part of any investigation into the unknown is running into dead ends. That's how science is done," says Emilio Emini, director of vaccine research for the International AIDS Vaccine Initiative. "It's not as if we're running out of ideas. Failures teach you to modify your path."
The vaccines now in trials include vaccines made with bits of pure genetic material from the AIDS virus, stripped of the sections that would allow HIV to reproduce itself and spring to life. These so-called DNA vaccines, once viewed as promising, have since proved disappointing. Others are Trojan-horse vaccines, made by stuffing viruses with inactivated HIV proteins that researchers hope will send the immune system into overdrive.
Many basic questions also remain unanswered. For instance, no one knows what immune responses best guard against HIV infection.
And no one has figured out how to produce a vaccine that can prompt the immune system to generate antibodies capable of killing the AIDS virus, before it establishes a toehold in the body. These so-called neutralizing antibodies are critical to the effectiveness of every other vaccine.
"A lot of labs are working very vigorously on this," says Paul Spearman of Vanderbilt University.
Most vaccines now in development activate a very different arm of the immune system, one designed to rid the body of infected cells. While these vaccines won't block infection, researchers hope they'll serve as a kind of immune therapy able to keep the virus in check, stave off symptoms and prolong life. Vaccines tested so far haven't produced a potent enough response.
Some human trials to watch are:
- A third test of AIDSVAX is now underway in Thailand, involving 16,000 people. This study uses AIDSVAX as a priming dose for a second prototype vaccine made from a combination of harmless HIV genes and canarypox virus by the drug firm Aventis. This study has been criticized as a waste of time and resources. "There is substantial evidence that this vaccine combination is not likely to be protective," says Charles Rinaldo of the University of Pittsburgh.
- A small-scale human effectiveness trial of a Merck vaccine slated to begin in about 1,500 people by the end of this year. Another Trojan-horse vaccine, it packages an HIV gene in an ordinary cold virus. Tests have shown such vaccines are safe, but they won't prevent infection. Instead, they help the immune system hold HIV in check.
- Preliminary tests of a prototype vaccine developed by the NIAID Vaccine Research Center. This one packages multiple HIV genes, from different strains of the virus, in genetically engineered cold viruses.
Spearman calls the latter vaccines the most exciting of those now in development.
When one approach doesn't work, drop it and move on, says IAVI director Seth Berkley. Berkley says he is poised to pull the plug on a once widely promoted vaccine his organization sponsored in trials in London and Nairobi, Kenya. Those studies found the vaccine activated the immune system in just 20 percent of those who received it.
There's no way to avoid such missteps because monkey studies of HIV vaccines have turned out to be powerless to predict how well the vaccines will work in humans.
The failure has prompted a profound shift in research strategy, says Lawrence Corey, director of the HIV Vaccine Trials Network.
Rather than winnowing out likely winners by testing them in animals, researchers are going to have to mount costlier small-scale trials in humans, Corey says.
It will take patience, says Gary Nabel director of the NIAID Vaccine Research Center. "Nothing happens overnight," he says, "especially in medicine."
Surge in arthritis expected to tax
From Canadian Press
Sep. 21, 2004.
Canada's health-care system could be debilitated by a predicted explosion in arthritis cases over the next 20 years unless steps are taken to bolster access to joint-replacement surgery and other treatments, a report profiling the disease in Ontario suggests.
The study by the Institute for Clinical Evaluative Studies (ICES) shows that wait times for surgeries to end the pain and disability of joints eroded by arthritis have been edging ever higher in Ontario: the average wait for a knee replacement jumped to 29 weeks in 2002 from 20 weeks in 1994, while the average queuing time for a hip replacement rose to 20 weeks from 16 weeks during the same period.
But one in five patients needing an artificial hip joint and more than one in four requiring a new knee waited more than a year for their operations, said the report released Tuesday. And the burden of the disease is expected to balloon in the next two decades, particularly as aging baby boomers begin to suffer from years of wear and tear on active joints.
"What applies in Ontario applies to the rest of Canada, and probably access to health care in some other parts of Canada may well be worse," said epidemiologist Elizabeth Badley, lead researcher of the study. "So if we have a problem here, we have a problem everywhere."
In Ontario, osteoarthritis and rheumatism affected more than 1.6 million people over age 15 in 2001; by 2026, that figure is predicted to jump to 2.8 million, the report says. Across Canada, the number of cases is expected to hit six million by 2026.
Patricia Cooper knows all too well the agony of arthritis and the frustration of waiting for a hip replacement.
The 51-year-old got an artificial joint for her left hip a year ago, but the surgery to replace its twin isn't scheduled until next March. In the meantime, Cooper has had to take a leave from her job as a real estate agent. She walks — when she's able — with canes or a walker, and she's often forced to live on one floor of her two-storey house because many days she can't manage stairs.
"The pain is ever-present, 24/7," Cooper said Tuesday from her home in Oakville, Ont., just west of Toronto. "It disturbs my sleep; I'm lucky to get a couple hours of sleep at a time, and that's with a mild sleeping aid.
"It's very upsetting because you cannot see a light at the end of the tunnel. You're not sure if it's going to be cancelled again," she said of the elective hip surgery. "You just end up becoming a decrepit home-bound person, and it changes your whole attitude.
"It changes everything about you."
Cooper is among about 28,000 Ontarians waiting for a joint replacement because of osteoarthritis.
But Badley, a senior scientist for ICES in Toronto, said the study shows that joint-replacement therapy — a radical treatment for end-stage osteoarthritis — ``is only the tip of the iceberg, that there are many more people who have arthritis that never come to (need) joint-replacement therapy."
Many with varying degrees of pain and restricted mobility often don't get properly diagnosed or treated.
"People think it's arthritis and it's growing old and nothing can be done; but it's not inevitably a part of growing old," said Badley. "There are almost one in 20 people out there who do have arthritis and it's a neglected area for intervention."
While cases soar, the numbers of rheumatologists, orthopedic surgeons, and physical and occupational therapists to diagnose and treat the disorder "have effectively remained static since 1997," said Jo-Anne Sobie, a Toronto-based spokeswoman for the Arthritis Society.
"So this is going to translate into seriously declining levels of services per individual as the number of people with arthritis rises in the future."
Access to prescription medicines was also dealt with by the report, which recommended that Ontario's drug benefit formulary reflect the increased demand for newer, more effective drugs for osteoarthritis.
And for those with rheumatoid arthritis, caused by the body's immune system going awry and attacking joints and tissue, the report calls on governments to make highly effective drugs known as DMARDS and biologics more readily available to doctors and to cover the costs for patients in need.
Biologics, which can halt the progression of the disease, cost up to $30,000 a year per patient. The price is high, but the number of patients is small, said Badley, noting that about 1,000 to 1,500 Ontarians would need the drug each year.
"There's no question that the costs of not providing people with these special drug therapies is a huge amount more in lost productivity and in disability, as these people are no longer able to be active members of society, they lose their jobs, they can't support their families," said Sobie.
"So the cost of not providing these drugs is even greater than the cost to provide them."
What's needed, said Badley, is a long-term, comprehensive strategy by governments, including training more specialists and other care providers to better understand, diagnose and treat this potentially crippling disease.
Merck Withdraws Arthritis Drug
Sep 30, 2004
NEW YORK (Reuters) - Merck & Co. (NYSE:MRK - news) said on Thursday withdrew its arthritis drug Vioxx globally after a colon cancer trial confirmed long-standing concerns the drug raises the risk of heart attack and stroke.
A recent study by the U.S. Food and Drug Administration suggested patients taking Vioxx faced a 50 percent greater risk of heart attacks and sudden cardiac death than those taking Pfizer Inc.'s rival Celebrex treatment.
Vioxx had sales last year of $2.55 billion. They have been flat in recent years amid ongoing safety concerns.
Merck's shares plunged in pre-market trading after the announcement.
Merck said it is withdrawing the drug following data from a new three-year trial of Vioxx, designed to evaluate the effectiveness of the drug's standard 25 milligram dose in preventing recurrence of colorectal polyps. Such polyps often become cancerous.
"In this study, there was an increased relative risk for confirmed cardiovascular events, such as heart attack and stroke, beginning after 18 months of treatment in the patients taking Vioxx compared to those taking placebo," Merck said in a release.
"It's a major blow for Merck," said Sena Lund, an analyst at Cathay Financial. "It was one of their five key drivers for future growth."
Merck had expected Vioxx to help restore the company's earnings growth when the drug was launched in 1999, but its sales have been hurt by clinical trial data showing it increased the incidence of blood clots tied to strokes and heart attacks.
Meanwhile, sales of Pfizer Inc.'s similar drugs, Celebrex and Bextra, have steadily grown as doctors have turned to those drugs, which have not been linked to heart attack and stroke.