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Ampligen, also known as poly I:poly C12U, is an experimental immunomodulatory double stranded RNA drug developed by Hemispherx Biopharma of Philadelphia, Pennsylvania. Ampligen was first synthesized in the 1970s and has been proposed and tested as a treatment for illnesses including chronic fatigue syndrome (CFS) and acquired immunodeficiency syndrome (AIDS).

Hemispherx reports that it completed a Phase III clinical trial for CFS in 2004 and filed a new drug application (NDA) with the U.S. Food and Drug Administration (FDA) to market and sell Ampligen for the treatment of CFS, but this was rejected in December 2009 because the FDA concluded that the two RCTs "did not provide credible evidence of efficacy."

History

Ampligen was developed in the 1960s after Merck & Co. synthesized a double-stranded RNA compound composed of inosinic and cytidylic acid residues (poly I:poly C or poly I:C). Poly I:C inhibited tumor growth by inducing interferon production. In the mid-1970s, William A. Carter, a post-doctoral researcher at Johns Hopkins University, modified the dsRNA molecule by adding uridylic acid molecules at specific interval along the RNA chain. The new compound, called Ampligen (for AMPLIfied GENetic activity) stimulated interferon production like poly I:C, but was less toxic. A new research project is about to commence on the use of Ampligen in the treatment of ME/CFS (chronic fatigue syndrome ). Key physicians have been recruited in this treatment project, Derek Enlander MD, New York, Charles Lapp MD, Carolina, Lucinda Bateman MD , Salt Lake City, Nancy Klimas MD Miami, and Dr Peterson MD Reno. The project is due to start in May 2011. Carter founded a company based upon the compound and licensed it from Johns Hopkins. By the late 1980s, Carter and his company, HEM Research, Inc., were pursuing human therapeutic uses for Ampligen, as well as non-therapeutic uses, such as diagnostic testing for HIV and protecting plants from pathogens.

Ampligen was tested in clinical trials in America beginning in 1988, after DuPont invested $30 million in Hemispherx. Initial success in a small trial for AIDS treatment 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.

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. 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. 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. The marketing agreement with Bioclones was terminated in 2005. 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).

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.

In 2009, William Carter said that Ampligen could be a booster for a flu vaccine to the H1N1 flu and fight the 2009 swine flu outbreak.

The FDA postponed an announcement about Ampligen scheduled for May 25, 2009 for "one to two weeks." In July, 2009, a report said that the FDA's decision would not be announced until later in 2009. Critics said that Hemispherx is regularly using "an eight year old government report to assure investors the company's chronic fatigue syndrome drug will be approved soon."

The drug was rejected by FDA in December 2009.

Hypothesized mechanism of action

The manufacturer says ampligen acts by stimulating the innate immune system. Cells normally encounter double-stranded RNA molecules like Ampligen and poly I:C only during infection with RNA viruses. A receptor on the cell surface called Toll-like receptor 3 (TLR3) is part of an evolutionarily conserved family of “pattern recognition” receptors that detect pathogens immediately, even those the body has not yet encountered, long before adaptive immunity can intervene against foreign invaders. These molecules are critical to the first line of immunological defense against a broad range of pathogens, such as viruses, and even various forms of cancer.

When TLR3 senses a dsRNA, it relays a message to the cell to produce interferon, a small protein that serves as a signal. Interferon alerts other cells that an infection is present and produces a series of responses in nearby cells and the interferon-producing cell. These include changes in gene regulation, for example stimulating production of the 2'-5' oligoadenylate synthetase-dependent enzyme RNase L (Ribonuclease, latent). This protein degrades viral RNA. It can also degrade the cell's own RNA, leading to the apoptosis (programmed cell death) of virally compromised cells.

The mechanism of Ampligen in relation to CFS is not known but it is thought to involve RNase L. Accumulation of an inactive form of RNase L may be associated with CFS. According to a Hemispherx press release summarizing findings published in the Journal of Immunology, Ampligen requires TLR-3 to work, in contrast to other synthetic dsRNA molecules that are detected by multiple cellular sensors.

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. The AMP 511 open-label study of Ampligen in CFS is still recruiting participants. 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. 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. In October 2007, the US Food and Drug Administration (FDA) Ampligen NDA was filed. In December 2009 the FDA issued a CRL refusing Hemisherx's new drug application for Ampligen's treatment of CFS. The FDA concluded that the two RCTs "did not provide credible evidence of efficacy." The agency recommends a minimum of one additional six month 300 patient study, and rodent carcinogenicity studies. The company reports it is currently working with the FDA to address these concerns.

Ampligen is received intravenously. It is generally administered twice weekly for periods of one year or greater. Two toxicology studies were recently completed that establish the safety of intranasal and intramucosal methods of Ampligen administration. Hemispherx states it is currently researching an oral drug that uses nucleic acid technology related to Ampligen.

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, 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.

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." 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. The extent of these side-effects is unknown. According to Hemispherx, side-effects usually subside within "several months".

Controversy

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.

Manuel Asensio, an investment adviser who reports on companies he considers to be overvalued, has criticized Hemispherx and its Ampligen results, alleging a variety of misdemeanors including accusations of refusing to supply Ampligen after clinical trials have ended, and issuing misleading results to widen markets for Ampligen.

In 1998, Hemispherx Biopharma filed a complaint against Asensio and his company, alleging defamation, conspiracy and interference with its business relations through a short selling plot. After a jury rejected the defamation claims against Asensio, a mistrial was declared. Hemispherx announced in 2006 that they anticipated a new trial date to be set.

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.

In June 2009, The Street alleged Hemispherx was "seeking to divert investors' attention away from the delayed approval of Ampligen as a treatment for chronic fatigue syndrome" by issuing three press releases in seven days about research from 2007 into possible applications for Ampligen as a flu vaccine booster. Hemispherx stated that Ampligen could be used against the H1N1 swine flu. The Street also alleged the Hemispherx press releases were misleading because they imply the research had been done in 2009. Hemispherx's attempts to put Ampligen in the H1N1 market were unsuccessful. The company stated they were "shut out of the U.S. government's efforts to stockpile vaccine against the H1N1 flu."

Other uses

The manufacturer says Ampligen can be used for Avian Flu and AIDS, although studies have been limited. Other suggested uses include Ebola and Smallpox.

See also

• Oragen

References

1. ^ Hemispherx Biopharma Files New Drug Application for Ampligen as Treatment of Chronic Fatigue Syndrome NDA of investigational drug includes four well-controlled trials, more than 1,200 trial subjects and 90,000 doses Cite error: The named reference "Hemispherx" was defined multiple times with different content (see the help page).
2. ^ George, John (Modified: Thursday, December 3, 2009). "FDA rejects Hemispherx's chronic fatigue drug Ampligen" (html). Philadelphia Business Journal. Retrieved 2010-02-12. {{cite web}}: Check date values in: |date= (help)
3. ^ http://www.thestreet.com/_yahoo/story/10636318/1/hemispherxs-ampligen-dealt-fda-blow.html
4. Kitei, Mindy. A History of Ampligen: The AIDS Drug No One Can Have." Philadelphia Magazine. October 1994. Retrieved on February 25, 2007.
5. "Business Description: HEM Research, Inc." 1986. Retrieved on February 25, 2007.
6. Johnson, Hillary. "Osler's Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic." 1996. Crown Publishing Group. Retrieved on February 25, 2007.
7. Melnyk, Eugene; Howling, Kenneth G. "Biovail Acquires Ampligen Marketing Rights for Canada; New Treatment for Chronic Fatigue Syndrome." Biovail. February 11, 2000. Retrieved on February 25, 2007.
8. "SEC Filing (Form S-3): Hemispherx Biopharma, Inc.." January 14, 2003. Retrieved on February 25, 2007.
9. "Mismatched Double-Stranded RNA: Ampligen, Oragen, Polyi:Polyc12u." Drugs in R&D. February 1, 2002. Retrieved on February 26, 2007.
10. "p. 35
11. "Securities and Exchange Commission
12. ^ "Hemispherx builds false hope on old data," Adam Feuerstein, The Street, June 5, 2009
13. "Hemispherx says FDA decision on Ampligen months away" John George, Philadelphia Business Journal, July 22, 2009
14. "Hemispherx Biopharma,HEB - Losing Ground" June 5, 2009
15. Suhadolnik RJ, Reichenbach NL, Hitzges P, Adelson ME, Peterson DL, Cheney P, Salvato P, Thompson C, Loveless M, Müller WE (1994). "Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome". In Vivo (Athens, Greece). 8 (4): 599–604. PMID 7893988.{{cite journal}}: CS1 maint: multiple names: authors list (link)
16. Nijs J, De Meirleir K (2005). "Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome". In Vivo. 19 (6): 1013–21. PMID 16277015.
17. Gowen BB, Wong MH, Jung KH; et al. (2007). "TLR3 is essential for the induction of protective immunity against Punta Toro Virus infection by the double-stranded RNA (dsRNA), poly(I:C12U), but not Poly(I:C): differential recognition of synthetic dsRNA molecules". J. Immunol. 178 (8): 5200–8. PMID 17404303. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
18. Edgar pro
19. ClinicalTrials.gov: Study of Ampligen in Chronic Fatigue Syndrome
20. fda.gov: Guidance for Institutional Review Boards and Clinical Investigators
21. Edgar pro
22. "Ampligen". Hemispherx Biopharma. Retrieved 2008-04-26.
23. http://sec.gov/Archives/edgar/data/946644/000114420407023929/v074337_10q.htm, p. 20
24. http://www.hemispherx.net/content/rnd/drug_candidates.htm
25. Abstracts of Papers Presented at The Bi-Annual Research Conference of the American Association for Chronic Fatigue Syndrome (AACFS)
26. Suhadolnik RJ, Reichenbach NL, Hitzges P; et al. (1994). "Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome". In Vivo. 8 (4): 599–604. PMID 7893988. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
27. Strayer DR, Carter WA, Brodsky I; et al. (1994). "A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome". Clin. Infect. Dis. 18 Suppl 1: S88–95. PMID 8148460. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
28. Mitchell, W. (2006). "Review of Ampligen clinical trials in Chronic Fatigue Syndrome". Journal of Clinical Virology. 37, supp. 1: S113. doi:10.1016/S1386-6532(06)70079-8. Retrieved 2007-02-26. {{cite journal}}: Unknown parameter |month= ignored (help)
29. Ampligen - official Hemispherx site
30. fda.gov
31. fda.gov
32. ^ Asensio & Company: Hemispherx Analyst Makes False Ampligen HIV Efficacy Claims Despite Failed Test and FDA Violation Notice
33. Ampligen: Excerpts from Osler's Web
34. Securities and Exchange Commission
35. U.S. Department of Health and Human Services: Chronic Fatigue Syndrome Advisory Committee (CFSAC)
36. "Hemispherx Not Among 4 to Get H1N1 Flu Contracts" Adam Feuerstein, The Street, July 14, 2009
37. "Hemispherx Presents Evidence of Ampligen Synergies with Existing Antivirals at International Avian Influenza Conference". BUSINESS WIRE. 2007-06-04. Retrieved 2008-04-26.
38. Alibek K, Liu G. (2006 May). "Biodefense shield and avian influenza". Letter. Emerg Infect Dis. Retrieved 2007-12-14. {{cite journal}}: Check date values in: |date= (help); Cite journal requires |journal= (help)
39. Hemispherix: The TLR3 Agonist, Poly I: Poly C12U, Provides Nasal Adjuvant Activity to a Vaccine Directed Against Highly Pathogenic H5N1 Avian Influenza Virus
40. ClinicalTrials.gov: The Role of Ampligen in Strategic Therapeutic Intervention (STI) of HAART
41. ClinicalTrials.gov: Safety and Efficacy of Ampligen in the Treatment of HIV Patients Failing HAART
42. Hemispherix: Product Candidates Under Development
43. wired.com: Smallpox Treatment or Snake Oil?

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

• Drugs not assigned an ATC code
• Immunostimulants
• Antivirals