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	Atvogen Poly(inosinic acid) poly(cytidylic(12), uridylic)acid
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status
Routes	IV

Ampligen, also known as Atvogen and polyI:polyC12U, is an experimental antiviral and immunomodulatory double stranded RNA drug developed by HEMISPHERx Biopharma, Inc. It is believed to be of use mainly in the treatment of Chronic Fatigue Syndrome (CFS) and HIV, and is subject to some controversy.

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.^[1]

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.^[2] In 1987, Dr. Carter made a presentation to Philip Morris USA suggesting the possible use of Ampligen in treating tobacco to make a safe cigarette.^[2]

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.^[3] 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.^[4]

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.^[5]

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.^[6]

Ampligen is currently undergoing clinical trials in the United States.^[7]

[edit] Mechanism of action

In a 1986 Business Description of Hem Research the mechanism of action of dsRNA is described as follows: "When introduced into the body, a dsRNA, as a large nucleic acid, will initiate a two step proces equivalent to an immune system response. The compound appears as a virus to the human immune system and thus induces a normal immune reaction, including the induction of various white blood cell activities and the production of the appropriate lymphokines. The reaction approximates a natural immune response in that the immune factors appear at their normal levels of concentration within the body.

The second step of this process results from the dsRNA chemical structure. Certain biological pathways which are set in motion during immune system reactions require the presence of a catalyst to complete the pathway. dsRNA's serve that catalyst function." ^[8]

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 increasingly shows that the upregulation of this pathway is an important factor in the development of CFS.^[9] 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]}. Ampligen must be received intravenously, but Hemispherx is researching an oral form of the drug.^[10] It is generally administered twice weekly for periods of one year or greater.

[edit] Clinical trials and approval status

The randomized segment of the AMP 516 Phase III clinical trial in the USA was completed in 2004.[1] At the moment, an Open Label Study of Ampligen in CFS is recruiting [2]. These 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.[3] American Food and Drug Administration (FDA) approval of Ampligen for the treatment of CFS is not yet available, and no New Drug Application (NDA) has yet been filed. Hemispherx management has most recently targeted mid-2007 for the completion of the filing a new drug application, having missed several target deadlines for an NDA filing in the past, including the end of 2005, the third quarter of 2006 and the first quarter of the year 2007.[4]

[edit] Impact

Approximately 760 patients have received Ampligen as part of clinical trials in the US, representing about 75,000 doses. Some patients have reported a complete recovery, with others reporting clear and measurable improvements [5], 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 [6][7]. 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" [8].

[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."^[11] A mild flushing reaction has occurred in about 15% of patients, and other reported side effects include flushing, chills, fever, malaise, leukopenia, neutropenia and leukocytosis. A full list is available on the Hemispherx website.^[12] The extent of these side effects is unknown. According to Hemispherx, side effects usually subside within "several months".

[edit] Controversy

Ampligen has been surrounded by controversy since it was first discovered, in particular as to why it never completed FDA trials despite showing definite improvements in a number of patients.

Ampligen's first and most famous detractor was "Asensio" [9][10]. 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 false and defamatory statements. The complaint further alleged that Asensio defamed and disparaged Hemispherx in furtherance of a manipulative, deceptive and unlawful short selling scheme in August and September, 1998. A jury verdict disallowed the claims against Hemispherx for defamation and disparagement and the court granted a directed verdict on the counterclaim. Hemispherx now 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)[11]. Asensio still maintains a website documenting its allegations regarding the company.[12]

The conflict with Asensio also dragged in surprising bystanders, including Oprah Winfrey, Securities and Exchange Commission Chairman Arthur Levitt and AIDS activist David Scondras. [13]

A stinging testimony before the Chronic Fatigue Syndrome Coordinating Committee (CFSCC) of the U.S. Department of Health and Human Services on November 2, 1999 raised the question why Ampligen had never been fast-tracked by the US public health authorities.[14]

Many patients have been skeptical of results or have reported difficulties with Hemispherx.[15][16]. The company has also been accused of promising patients Ampligen free of charge when studies ended, but then refusing to supply it and pointing out that there is no mention of this claim in legal documents. [17]

According to Hemispherx, some trials have been poorly controlled and, accordingly, additional tests will be necessary for support of regulatory approvals. [18]

There have also been accusations that Hemispherx issue misleading results [19] in attempts to create a wider market for their drugs, although this has never been proven.

It has on two occasions received warning letters from the FDA regarding its promotion of Ampligen as safe and effective before approval from the FDA.[20][21]

In spite of all the controversy, Hemispherx Biopharma has never, by a judgement which has the force of res judicata, been found guilty of illegal behaviour.

[edit] Other uses

Some alternative potential uses of Ampligen include fighting Avian Flu^[13], [22] [23], AIDS [24], [25],[26], Hepatitis B and Cancer, although studies have been limited. [27] Other suggested uses include Ebola and Small Pox. [28] 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. [29]

[edit] See also

• Chronic Fatigue Syndrome
• Oragen

[edit] References

[edit] External links

• Ampligen FAQ (1996)
• Ampligen Debate
• 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
• Stock Lemon (2002)
• Motley Fool (2002)