Ampligen

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Ampligen
Systematic (IUPAC) name
5'-Inosinic acid, homopolymer, complex with 5'-cytidylic acid polymer with 5'-uridylic acid (1:1)
Identifiers
CAS number	38640-92-5
ATC code	?
PubChem	38077
Chemical data
Formula	C28H40N9O25P3
Mol. mass	995.584
Synonyms	PolyI:PolyC12U
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status
Routes	IV

Ampligen, also known as polyI:polyC12U, is an experimental antiviral and immunomodulatory double stranded RNA drug developed by HEMISPHERx Biopharma of Philadelphia, PA. Ampligen was initially invented in the early 1970's and has been proposed and tested as a treatment for many illnesses, but primarily chronic fatigue syndrome (ME/CFS) and acquired immunodeficiency syndrome (AIDS).

In August 2004, Hemispherx completed a Phase III clinical trial, AMP 516, treating over 230 ME/CFS patients with Ampligen. A new drug application (NDA) for Ampligen in the treatment of CFS has been submitted to the FDA.^[1] To date, it has not been approved for marketing.^[2]

Contents 1 History 2 Mechanism of action 3 Clinical trials and approval status 4 Impact 5 Side effects and safety 6 Controversy 7 Other uses 8 See also 9 References 10 External links

[edit] History

Ampligen was developed in the 1960s after Merck & Co. had discovered a double-stranded RNA compound that inhibited tumor growth and induced interferon production. In the mid-1970s, Johns Hopkins University researchers redesigned the dsRNA molecule to overcome the toxicities of the Merck compound. By adding a small uridylic acid molecule at a specific interval along the molecule chain, the compound was detoxified, and Ampligen (AMPLIfied GENetic activity) was born.^[3]

In the late 1980s, Dr. Carter and his company, Hemispherx Research, Inc., were pursuing human therapeutic uses for Ampligen, as well as non-therapeutic uses, such as diagnostic testing for HIV and plant protections from pathogens.^[4]

Ampligen was first used in major clinical trials in America in early 1988, after DuPont had invested $30 million in Hemispherx. Initial success was followed by difficulties in persuading the FDA to permit large scale trials. By 1991, it was thought that the chance of approval for a large trial being conducted in the USA had gone. Hemispherx then began to move clinical trials to Canada and Belgium.^[5]

In Belgium, Ampligen has been available for use since the drug's trial beginning in May 1996. It has also been available under Canada's Emergency Drug Release Program for both Chronic Fatigue Syndrome (CFS) and HIV treatment since 1996, with marketing rights controlled by Biovail Corporation International.^[6] An agreement between the Spanish company Esteve and Hemispherx in 2002 gave Esteve the rights to perform clinical trials at their own cost in Spain, Portugal, and Andorra.^[7] Bioclones (PTY) Ltd, a UK based company, was granted the exclusive marketing rights to Ampligen in the United Kingdom, Ireland, and several countries in the Southern Hemisphere.^[8] The marketing agreement with Bioclones was terminated in 2005.^[9] Over its developmental history, Ampligen has received various designations, including “orphan drug product” and “emergency compassionate cost recovery sales authorization” both from the FDA and "promising" clinical outcome recognition based on the evaluation of certain summary clinical reports (AHRQ, Agency Health Research Quality).^[10]

On December 3, 2007, the FDA deemed the NDA submitted by the company on October 10, 2007 to be incomplete. Specifically eleven deficiencies were noted in the Clinical Section and three in the Pre-Clinical Section.

[edit] Mechanism of action

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The mechanism of action in relation to CFS is not entirely clear, but it is known to act on two important enzyme systems, one of which is the 2-5 Synthetase/RNase L anti-viral pathway. Research suggests that the upregulation of this pathway is an important factor in the development of CFS.^[11] The downregulation of this pathway leads to the immune system being better able to destroy viral RNA and accelerates the apoptosis of virally compromised cells^{[citation needed]}.

dsRNA is a large nucleic acid and initiates a two step process in the immune system. The compound appears as a virus and induces white blood cell activities, and also sets in motion certain biological pathways, where dsRNA serves as the catalyst. [1]

A Hemispherx press release dated April 30, 2007^[1] summarized April 2007 findings^[12] published in the Journal of Immunology on Ampligen’s mechanism of action. The biologic properties of Ampligen are conveyed exclusively by a unique naturally occurring receptor on the cell surface called “TLR-3.” Toll-like receptors (or “TLRs”) such as TLR-3 serve as “pattern recognition” receptors in the early detection of pathogens and the establishment of early defense mechanisms (innate immunity). As such, they are critical to the first line of immunological defense against a broad range of pathogens, such as otherwise lethal viruses and even various forms of cancer.

When the dormant alarm signals of TLRs are activated (as by exposure to a pathogen or a stimulant agent such as Ampligen), TLRs in effect cause an overreaction, driving the body to proliferate broad-spectrum defenses against many types of pathogens.

New research shows that these receptors present in virtually all life forms, from mosquitoes to man. In scientific terms, they are said to be remarkably “evolutionarily conserved.” This suggests that TLRs are critical to retaining healthy life in a constantly changing environment full of hostile pathogens, many of which the subject has never encountered before.

[edit] Clinical trials and approval status

A randomized study of Ampligen (AMP 516 Phase III clinical trial for treatment of CFS) in the USA was completed in 2004.[2] The AMP 511 open label study of Ampligen in CFS is still recruiting participants. [3] Open label studies are typically used when the controlled trial has ended and treatment is continued so that the subjects and the controls may continue to receive the benefits of the investigational drug until marketing approval is obtained.[4] Hemispherx management had missed several target deadlines for new drug application (NDA) filing in the past, including the end of 2005, the third quarter of 2006, and the first quarter of the year 2007.[5] In October 2007, the US Food and Drug Administration (FDA) Ampligen NDA was filed, but marketing for the treatment of CFS has not yet been approved.^[1][2]

Ampligen is received intravenously. It is generally administered twice weekly for periods of one year or greater. Hemispherx is researching an oral form of the drug.^[13] Two toxicology studies were recently completed that establish the safety of intranasal and intramucosal methods of Ampligen administration.^[14]

[edit] Impact

Approximately 760 patients have received Ampligen as part of clinical trials in the US, representing about 75,000 doses. Some Chronic Fatigue Syndrome patients have reported a complete recovery, with others reporting clear and measurable improvements [6], although success has not been universal. More common benefits include improved cognitive skills, an increase in energy, and greater oxygen uptake. These improvements can be measured on the Karnofsky scale [7][8]. Some studies suggest that Ampligen is most effective against a certain subset of CFS patients, those with severe debilitation^{[citation needed]}. According to Dr Paul Cheney, a CFS researcher, the chances of a response appear to be "2 chances in 3 and that might be raised a little bit if one targets a subset of patients, specifically ones that are within the first 5 years of their illness who have abrupt onset and who may have activation of this RNase L pathway" [9].

In December, 2006, Hemispherx reported results of a completed Phase 3 trial, in which chronic fatigue syndrome patients receiving Ampligen for 40 weeks “improved exercise treadmill performance 14.8% in the placebo group (p=0.025) and 13% by intent to treat analysis (p=0.052). The Ampligen group improved oxygen utilization by 6.1% v 0.58% in the placebo group (p<0.05, single-sided). The correlation with treadmill exercise duration in patients treated with Ampligen was highly significant (p<0.0001). The KPS (Karnofsky performance score), a function of general physical capacity, was also significantly correlated (<0.01) with the improvement in exercise tolerance of the Ampligen study arm … The concomitant use of drugs with Ampligen or placebo was reduced significantly in the Ampligen arm of both the Phase 2 and Phase 3 trials.”^[1]

[edit] Side effects and safety

Hemispherx consider that Ampligen has been "generally well tolerated", with a "low incidence of clinical toxicity", particularly when compared to the toxicity of the diseases it is used to treat. "No serious safety issues have resulted from the administration of ~75,000 doses IV (most commonly 400 mg) twice weekly for up to one year periods or greater. Animal toxicity studies support this observation in humans with primates demonstrating the greatest margin of safety."^[15] A mild flushing reaction has occurred in about 15% of patients, and other reported side effects include chills, fever, malaise, leukopenia, neutropenia and leukocytosis. A full list is available on the Hemispherx website.^[16] The extent of these side effects is unknown. According to Hemispherx, side effects usually subside within "several months".

One patient with CFS in the San Diego Ampligen study committed suicide during the clinical trial. Another quit because of serious side effects.^{[citation needed]}

[edit] Controversy

Ampligen's first and most famous detractor was Manuel Asensio [10][11]. On September 30, 1998, Hemispherx Biopharma filed a multi-count complaint against Manuel P. Asensio, Asensio & Company, Inc. The action included claims of defamation, disparagement, tortuous interference with existing and prospective business relations and conspiracy, arising out of Asensio's alleged false and defamatory statements. The complaint further alleged that Asensio defamed and disparaged Hemispherx in furtherance of an unlawful short selling scheme in August and September, 1998. A jury verdict rejected certain claims against Asensio for defamation and a mistrial was declared by Judge Shepard of the Philadelphia Court of Common Pleas. Hemispherx announced in 2006 that they anticipate the scheduling of a new trial against Asensio for defamation and disparagement in the Philadelphia Common Pleas Court (10Q September 30, 2006, p.33)[12]. Asensio had his broker's license permanently revoked by the NASD in August 2006 for "false and defamatory" research reports and paid several hundred thousand dollars in fines to the NASD for similar infractions. For a complete analysis of various corporate claims against Asensio, see the web site titled AsensioExposed.com.

On November 2, 1999, Mary Schweitzer, a Chronic Fatigue Syndrome patient who had been treated with Ampligen, raised the question of why Ampligen had never been fast-tracked by the US public health authorities at the Chronic Fatigue Syndrome Co-ordinating Committee of the U.S. Department of Health and Human Services. [13] After Dr. Schweitzer's inquiry and upon further deliberation the FDA grated Hemispherx an emergency or compassionate use authorization for the cost recovery sale of Ampligen to severely debilitated CFS patients who did not qualify for clinical trials. Dr. Schweitzer herself continues to receive Ampligen through a cost-recovery study.^[17] As of mid-2007, hundreds of patients in the U.S., Canada, Europe and the Southern Hemisphere (including Australia) have participated in these programs. Ampligen is the only such drug to have received this designation by a recognized regulatory authority worldwide.

Hemispherx has been accused by Manuel Asensio of a variety of misdemeanours involving Ampligen, including accusations of refusing to supply Ampligen after clinical trials have ended [14], and issuing misleading results to widen markets for Ampligen [15]. Hemispherx has on two occasions received warning letters from the FDA regarding its promotion of Ampligen as safe and effective before approval from the FDA.[16][17].

[edit] Other uses

Some alternative potential uses of Ampligen include fighting Avian Flu,^[18][19] [18] [19], AIDS [20], [21],[22], Hepatitis B and Cancer, although studies have been limited. [23] Other suggested uses include Ebola and Small Pox. [24] Research by Bioclones (PTY) Ltd in collaboration with the University of Wales College of Medicine has suggested that Ampligen is also a powerful inducer of dendritic cell maturation. [25]

[edit] See also

• Chronic Fatigue Syndrome
• Oragen

[edit] References

[edit] External links

• Ampligen FAQ (1996)
• Hemispherx Ampligen Page
• A History of Ampligen and its Creator
• Esteve Home Page
• Bioclones Ampligen Page
• Review of ampligen clinical trials in CFS
• Hemispherx Biopharma SEC filings
• Peer-reviewed Ampligen for CFS phase II trial article in Clinical Infectious Diseases 1994; 18 (Suppl. 1):S 88-95