Ampligen Finally Breaks Free of Red Tape -- in Canada
With permission from ChronicIllnet, 1997
It has been a decade, nearly to the day, since the first study demonstrated that the experimental drug Ampligen improved both the clinical health and immune status of AIDS patients. During that long decade, the Ampligen story has taken enough twists and turns to confuse Machiavelli and to drive patients in need of it to despair. The story of Ampligen mirrors that of the AIDS epidemic itself, involving corporate greed, malfeasance, and incompetence; scientific naivete (at best); governmental bungling; and, most importantly, the potentially needless suffering of probably millions of Americans. The tragedy is compounded by the fact that follow-on studies, eked out of non-existent budgets by struggling scientists and a small company on the edge of extinction, have shown that Ampligen also improves the health and well-being of patients with chronic diseases, including some forms of cancer, hepatitis, and Chronic Fatigue Syndrome.
The good news is that the waiting may now be over -- for those able to procure, and to afford, the drug.
Not only has Ampligen been approved for Phase III clinical testing in a small group of CFS patients in the U.S., it is now available (by prescription) in Canada to patients diagnosed as being HIV-positive, as well as those with CFS, under an emergency drug release statute. While CFS and AIDS patients are the focus of these two initiatives, evidence is accumulating to show that Ampligen is also beneficial to hepatitis B and C patients, as well as kidney cancer (renal cell carcinoma) patients. Furthermore, drug company scientists have suggested that Ampligen may also be beneficial to people suffering from Gulf War Syndrome, which has been repeatedly compared, in terms of symptomoloy, to CFS.
On May 7, the U.S. Food and Drug Administration authorized Ampligen's manufacturer, Hemispherx Biopharma Inc. in Philadelphia (formerly HEM Pharmaceuticals), to charge for Ampligen on a "cost recovery basis" while using it in an open-label clinical trial for Chronic Fatigue Syndrome (CFS). An open-label trial is one in which there is no placebo, or control, group; everyone in the trial will receive the drug. The Reuter news agency reported May 7 that the open-label trial, involving 20 patients, will begin immediately.
Hemispherx will also conduct a placebo-controlled trial in CFS patients in the near future; the protocol for that trial is being developed with the FDA.
As PRNewswire reported May 7, Hemispherx is the only company in the U.S. to apply to the FDA to test a treatment for CFS at the Phase III (efficacy) level. There are "an estimated 500,000 or more CFS/CFIDS sufferers in the United States alone," the story pointed out.
In Canada, Hemispherx's Ampligen has been available since late 1996 under the Emergency Drug Release Program, which allows physicians to prescribe drugs not yet approved by the Health Protection Branch (the Canadian drug regulatory agency), in instances in which there is a serious disease for which no effective treatment is available. Ampligen is provided to physicians by the Canadian firm Helix BioPharma Corp. (in Richmond, British Columbia) under the terms of a "strategic alliance" with Hemispherx, as the two companies announced on November 21, 1996. Helix BioPharma Corp. will be the exclusive distributor of Ampligen in Canada; the company develops, licenses, markets, and distributes biomedical and pharmaceutical products, technologies, and services in Canada and internationally.
The Ampligen alliance resulted in a favorable stock forecast and a "buy" rating for Helix BioPharma from Canadian corporate analysts Griffiths McBurney & Partners (following Fiscal Year 1996, ending July 31).
Ampligen "is administrated twice a week though an intravenous infusion that can be done on an out-patient basis, and is expected to be priced at US$18,000 to US$20,000 per year to the end user, excluding administration cost," the Griffiths McBurney & Partners report stated. "The price tag would appear prohibitive. However, because of the lack of an effective treatment for CFS, which affects an estimated 400,000 people in the United States alone, and the debilitating nature of the condition, individuals who can afford the treatment may be willing to pay. The availability of Ampligen in Canada could attract CFS sufferers from the United States and European countries, where the drug is currently unavailable. Over the next 12 to 18 months, the attraction of Ampligen for non-Canadian residents could lead to millions of dollars in total sales and a significant operating profit for Helix. Once Ampligen begins to receive marketing approvals and becomes available in the U.S. and Europe, the loss of non-Canadian patients could be offset, to a certain degree, by an increase in Canadian CFS patients. Although this drug appears to be a promising immune modulator with good upside potential, acceptance is uncertain at this stage because the product is new and expensive...."
The results of two recent studies of Ampligen's effects -- one in CFS patients, and the other in AIDS patients -- appear to have encouraged renewed activity on the Ampligen front.
The study of CFS patients was conducted in Belgium and was reported October 15, 1996, at the annual meeting of the American Association for Chronic Fatigue Syndrome (AACFS). The study found that Ampligen produced significant physical and cognitive improvements among patients suffering from CFS, and suggested as much as 80 percent recovery among patients treated with Ampligen. The study was presented by University of Brussels researcher Kenney De Meirleir, M.D., Ph.D., and David Strayer, M.D., one of the foremost experts on Ampligen in the United States. Dr. Strayer is currently Professor of Medicine at Allegheny University, PA, as well as Medical Director at Hemispherx.
In January 1997, Hemispherx announced that a new Phase II clinical trial of the effect of Ampligen on HIV viral load had begun at the University of Texas Health Science Center under the supervision of Dr. Patricia Salvato. The new Phase II trial will test the efficacy of Ampligen in HIV-positive patients with CD4 cell counts of more than 400 who are not being treated with any other medications.
The fact that Ampligen alone is being tested in HIV-positive patients is a critical breakthrough. The clinical trial on which the 1997 Texas trial is based tested the effect of Ampligen -- a safe drug with virtually no side effects -- used in conjunction with AZT, an incredibly toxic drug that many patients cannot tolerate. Even when AZT was included with Ampligen treatment, however, patients receiving it were found to be less likely to develop AIDS than patients who were treated with a placebo substance (published in the July 1996 European Journal of Microbiology and Infectious Diseases).
Ampligen-only therapy has also been shown to restore cell-mediated immunity, the ability to make antibodies in response to antigenic stimulation; the loss of cell-mediated immunity in AIDS patients can lead to an inability to fight even common infections. Although Ampligen-AZT therapy showed a similar result, AZT-only treatment is unable to restore cell-mediated immunity (also called "delayed-type hypersensitivity").
Hemispherx scientists reported these findings at the University of California's Fourth Annual "Frontiers of HIV Therapy" conference on March 8, 1996. Hemispherx reported that Ampligen, tested in conjunction with AZT, appeared to repair the delayed-type hypersensitivity (DTH) response that allows appropriate reactions to antibody-inducing agents such as tuberculosis. DTH is often tested by injecting small amounts of the antigen under the skin, as in the traditional tuberculosis skin test. If the portion of the immune system that produces the DTH response has been disabled -- by AIDS, cancer, or chronic fatigue syndrome, for instance -- then the person will not mount an antibody response to the antigen. (Delayed-type hypersensitivity, or DTH, is often used interchangeably with "cell-mediated immunity.")
The restoration of the DTH response is suggested, by investigators studying the "Theta Switch" theory of AIDS survival, to be of crucial importance in determining who is a long-term survivor of AIDS. In the Ampligen/AZT study, a "significant percentage" of 70 trial participants switched from unresponsive to responsive; AZT alone did not result in significant changes from unresponsive to responsive. According to a May 16, 1996, report of the study in Doctor's Guide (an internet magazine for physicians published by P\S\L Consulting Group Inc., sponsored by numerous international pharmaceutical companies), "Results of research conducted by the U.S. military suggest that HIV-infected subjects' median survival advantage may shift from 34 months to 69 months, apparently as a direct result of Theta switching."
In other words: Not only does Ampligen restore an important part of the immune system destroyed by AIDS, it appears to provide a geniune survival advantage.
The only problem is, Ampligen's efficacy was pretty-well defined a decade ago. How many people could have been helped in those intervening ten years, had Ampligen been approved by the FDA in 45 days, as was the first protease inhibitor?
The July 17, 1987, issue of The Lancet reported a trial of Ampligen in ten people with AIDS or "AIDS related complex" (The Lancet, 1987, 1:1286-1292).
"The drug was well tolerated," William A. Carter (Ampligen's co-inventor), David Strayer, and colleagues reported of their 1987 trial. "Clinical improvement occurred in all ten patients; those with AIDS-related syndromes had more striking responses than those with AIDS. HIV RNA was detected in the circulating blood cells of nine of the ten patients before therapy, but became undetectable in these nine after treatment. Cellular immunity [i.e., delayed-type hypersensitivity] improved in all ten patients. Furthermore, levels of helper-inducer T-lymphocytes and neutralizing HIV antibodies were maintained or increased."
In other words, ten years ago it was discovered that: Ampligen decreases HIV viral load; restores cell-mediated immunity; increases (or stops destruction of) HIV neutralizing antibodies; increases (or stops the depletion of) CD4 cells; improves clinical status; and is most effective when administered in the early stages of AIDS.
Although this was only one, very small, study, it was right on the money; its results have been supported by further research.
One tragedy of those nearly-lost ten years is the proliferation of chronic "mystery" diseases, like Chronic Fatigue Syndrome, in which Ampligen may prove to be efficacious. Even Gulf War Syndrome patients may benefit from Ampligen treatment, as Hemispherx officials have suggested. A study published in the January 15, 1997, Journal of the American Medical Association found a greatly increased percentage of Gulf War veterans suffered from cognitive difficulties and fibromyalgia -- which most investigators now recognize is a type of CFS -- than do other military personnel.
David. A Schwartz and colleagues at the University of Iowa College of Medicine surveyed (by telephone) 3,695 deployed and non-deployed military personnel based in Iowa (a "population-based" survey).
"Compared with non-Persian Gulf War military personnel, Persian Gulf War military personnel reported an 11 percent higher prevalence of symptoms of cognitive dysfunction; a nine percent higher prevalence of symptoms of fibromyalgia," among numerous other symptoms surveyed, Schwartz reported, including depression, anxiety, alcohol abuse, and post traumatic stress disorder (JAMA 277:238-245, 1997).
Unfortunately, Schwartz's study implies that the symptoms of Gulf War Syndrome are a) not unique to the Persian Gulf War, but have existed since modern warfare developed, and b) are generally psychiatric in origin. These are precisely the arguments some researchers have advanced to explain -- or, perhaps more accurately, explain away -- CFS. Perhaps that's simply another reason to treat veterans with Gulf War illnesses with a drug that appears to be efficacious for CFS patients.How Ampligen Works
Ampligen is a mis-matched, double-stranded RNA (abbreviated "dsRNA") described by Hemispherx as a "second generation" interferon; it has broad-spectrum anti-viral and immune modulating properties. Currently, Ampligen must be administered intravenously (IV), but Hemispherx is collaborating with researchers at Temple University (Philadelphia) to develop a pill form of the drug.
Ampligen is an actively anti-viral compound; it has been shown to stop the replication of a virus that infects both AIDS and CFS patients, Human Herpes Virus 6 (HHV-6). In fact, when cells are grown in culture with Ampligen and HHV-6, the drug blocks the virus from even infecting the cells (Ablashi, D.V. et al.; "Ampligen Inhibits Human Herpesvirus 6 In Vitro"; in vivo 8:587, 1994).
In various clinical trials, Ampligen has been shown to boost immunity (as measured by increased CD4 cell counts and restored cell-mediated immunity), dramatically increase the Karnofsky Performance Score (which measures ability to perform the activities of daily living) in treated individuals, and to restore cognitive functioning, even in patients who have experienced a measurable decrease in IQ (Strayer, David et al.; "Long Term Improvements in Patients With Chronic Fatigue Syndrome Treated With Ampligen"; Journal of Chronic Fatigue Syndrome 1(1):35, 1995). In addition to its other immunological effects, Ampligen has been shown to boost natural killer (NK) cell and monocyte activity. Both are scavenger cells that attack other cells recognized to be infected by pathogens or are otherwise abnormal (like cancer cells); NK cells are non-specific scavengers, while monocytes are usually more specific hunters (Suhadolnik, Robert J. et al.; "Upregulation of the 2-5A Synthetase/RNase L Antiviral Pathway Associated With Chronic Fatigue Syndrome"; Clinical Infectious Diseases, January 1994).
Unlike most of the anti-viral drugs currently in use, Ampligen has virtually no side effects. In a long-term study of Ampligen treatment of 15 CFS patients, the only adverse events linked to Ampligen were lightheadedness (one case) and facial flushing (one case). There were no changes in laboratory blood test values, blood clotting, or urinalysis test values (Strayer, David et al.; "Long Term Improvements in Patients With Chronic Fatigue Syndrome Treated With Ampligen"; Journal of Chronic Fatigue Syndrome 1(1):35, 1995).
Ampligen has been studied perhaps in the greatest detail by Temple University School of Medicine researcher Robert J. Suhadolnik and his colleagues. Suhadolnik has deconstructed the 2-5A synthetase/RNase L pathway, a naturally-existing anti-viral pathway found in all mammals, and examined Ampligen's effect upon it.
The 2-5A synthetase/RNase L pathway is actually a complex biochemical reaction. Very simplistically, it works like this: The pathway, when it is functioning properly, is activated primarily by viral infection. Upon activation of the pathway, the substance 2-5A synthetase converts ATP (a source of cellular energy) to 2-5A (which stands for 2'-5'-oligoadenylate). The 2-5A activates RNase L; finally, the 2-5A synthetase/RNase L pathway is completed, and RNase L attacks both cellular and viral single-stranded RNA. Since single-stranded RNA is involved in viral growth, this action is the source of the pathway's anti-viral property.
Suhadolnik and colleagues studied the 2-5A synthetase/RNase L pathway in both CFS and AIDS patients. In CFS patients, the pathway is "upregulated," according to these investigators; that is, too much of the end product, RNase L, is produced. In AIDS patients, the 2-5A synthetase/RNase L pathway is "downregulated"; not enough 2-5A synthetase is produced to spark the pathway's biochemical reaction. (Suhadolnik noted, however, that some CFS patients' pathways exactly resembled those of AIDS patients'. This distinction between CFS and AIDS patients' immune functioning may, therefore, turn out to be false, or to be a function of the stage of disease at which patients are tested.)
The remarkable effect of Ampligen is to correct the 2-5A synthetase/RNase L pathway: Whether it is upregulated or downregulated, Ampligen restores its functioning to normal. Because of this dual action, Ampligen is called an "allosteric modifier."
Correcting the functioning of the 2-5A synthetase/RNase L pathway results in the "clinical improvements" that occur during Ampligen therapy, Suhadolnik and colleagues conclude, but they do not presume to state they understand all of the biochemical effects Ampligen produces in the human body.Patient Zero
In early 1990, this reporter interviewed Ampligen "Patient Zero," Nancy Kaiser, who described her life before Ampligen. Kaiser first became ill from what would turn out to be Chronic Fatigue Syndrome in the late 1970s. From being a very athletic person who played golf four times a week and went swimming every morning, Kaiser was transformed into some who could not even walk the golf course because of a painful, burning sensation in her feet and legs. She also developed a strange constellation of symptoms: a rash on her eyelids, impaired vision, disturbed thought processes, chronic bladder and yeast infections, and chronic pelvic pain.
"Various doctors told me I was going through an early menopause, I was upset because my children were growing up, I had an unhappy marriage," Kaiser recalls. "None of it was true. I was sick."
After years of unsatisfactory and unhelpful medical treatments (including an unnecessary hysterectomy), Kaiser finally found Dr. Daniel Peterson, one of the physicians who had identified the first outbreak of CFS in Incline Village, Nevada, in 1984.
"Dr. Peterson told me, 'You're not crazy. You're very, very sick.' He was the first doctor who didn't think I had a psychiatric illness," Kaiser now says.
Peterson, with the help of Senator Pete Domenici, lobbied the FDA to release Ampligen to treat Kaiser under a compassionate care plea. In 1988, FDA granted the request, and HEM Pharmaceuticals (the precursor to Hemispherx) supplied Kaiser with Ampligen at no charge for several years.
While waiting for the FDA to act, Kaiser became deathly ill. By the time Ampligen was available to her, she was having 12-15 seizures every day. She couldn't walk; "I had to crawl," she says. Kaiser couldn't even feed herself when she finally traveled to Incline Village to be treated with Ampligen by Peterson.
"Three months after the first treatment, I could go home to my husband. I have had no infections at all since I started getting Ampligen," Kaiser said in 1990. "I never had any serious side effects -- just slight chills and occasional nausea while getting the drug [intravenously]."
Kaiser's astonishing response to Ampligen convinced the FDA to allow Peterson to conduct the first, 15-person clinical trial of Ampligen in CFS patients. Kaiser herself credits the drug with saving her life.
Kaiser knows she was, ultimately, extremely lucky. Many thousands of patients could probably benefit almost as much as Kaiser from Ampligen treatment, but will it ever be made generally available in this country?
Hemispherx, the company formed as HEM Pharmaceuticals by Ampligen co-inventor William Carter, has persevered through financial hard times, near-fatal interference by larger pharmaceutical companies, FDA indifference, and even the anger of CFS patients who know simply that they need the drug that Hemispherx should be able to manufacture and market. Now that the tide appears to have turned a bit in Ampligen's favor, hopefully Hemispherx will make all reasonable attempts to manufacture Ampligen so that it can be available to all who need it, not just the wealthiest among them.